The present invention relates to bioadhesive, closed-cell foam film, sustained release, delivery devices for administering an active agent or combination of active agents to a subject. The present invention also relates to methods for making such delivery devices and to methods for using such bioadhesive delivery devices to provide a sustained, controlled release of an active agent or combination of active agents to a subject, preferably a near zero-order release of the active agent or combination of active agents.
Prescription and over-the-counter medications and other pharmaceutical products have traditionally been administered through oral ingestion, nasal sprays, injections and suppositories. For example, many pharmaceutical dosage forms are administrated orally in the form of solid shaped articles such as tablets, pills, caplets and capsules that retain their shape under moderate pressure. Generally these dosage forms are designed to be swallowed whole or chewed to deliver the medication with adequate amounts of liquid. Some patients, particularly pediatric and geriatric patients, have difficulty swallowing or chewing such solid dosage forms. Certain patients such as children or animals often resist taking medications, and may try to hide such dosage forms in order to spit it out later. In addition, many pediatric and geriatric patients are unwilling to take such solid dosage forms because they have difficulty swallowing them even when liquids are consumed therewith. Furthermore, the availability of liquids at the time of administering medications may be limited for certain patients and may be restricted for certain diseases and/or treatments.
Chewable tablets provide some advantages over conventional tablets. Such chewable tablets, however, are not suitable for children wearing braces and the taste of certain active agents may be unpleasant and difficult to mask in a chewable tablet. In addition, the use of chewable tablets may not eliminate the desire or need to administer water or some other liquid therewith.
Furthermore, the standard oral dosage forms, such as tablets, pills, caplets, and capsules, are designed for short residence time in the mouth. Absorption of the active agent from these dosage forms typically occurs in the gastrointestinal (GI) tract, after the active agent has separated from the dosage form and dissolved in the gastric fluids. For some active agents, it is desirable to achieve absorption through a mucosal tissue in order to accelerate onset of the therapeutic effect.
Many active agents are poorly absorbed, even after they are dispersed in the stomach, because of low solubility or slow dissolution rate in the gastric fluids. Tablets may be formulated so as to be quick dissolving. These tablets are commonly placed on the tongue and disintegrate rapidly in the oral cavity. These dosage forms, however, are not fixed to a mucosal tissue and may move around in the mouth. Consequently, these dosage forms do not overcome the risk associated with choking or gagging that occurs with subjects having limited control of their swallowing reflexes.
Accordingly, what is needed are bioadhesive delivery devices which provide for the sustained, controlled release of an active agent or combination of active agents to a subject, which delivery devices are easy to use and are comfortable while in place in a subject.
The following definitions are provided to facilitate an understanding of certain terms used frequently herein.
The term xe2x80x9cbioadhesive delivery devicexe2x80x9d as used herein and in the appended claims means any solid substance, of any shape, which is intended to be adhered to a mucosal tissue of a subject. The term xe2x80x9cbuccal devicexe2x80x9d or xe2x80x9cbuccal delivery devicexe2x80x9d means a bioadhesive device which is intended to be inserted into the buccal cavity. The term xe2x80x9cvaginal devicexe2x80x9d or xe2x80x9cvaginal delivery devicexe2x80x9d means a bioadhesive device which is intended to be inserted into the vagina.
The term xe2x80x9cbioadhesive, closed-cell foam film, sustained release, delivery devicexe2x80x9d as used herein and in the appended claims means a bioadhesive delivery device comprising a closed-cell foam film substance designed to provide a sustained, controlled release an active agent or combination of active agents to a subject. These bioadhesive delivery devices preferably include buccal delivery devices and vaginal delivery devices.
The term xe2x80x9ccontrolled releasexe2x80x9d as used herein and in the appended claims means that a predetermined dosage of an active agent or combination of active agents is administered to a subject over a period of time.
The term xe2x80x9cbioadhesive forcexe2x80x9d as used herein and in the appended claims is a quantitative value for tackiness (grams) which simulates the adhesion of the bioadhesive, closed-cell foam film, sustained release, delivery devices of the present invention upon contact with a moist mucosal tissue. The bioadhesive force preferably should be at least 10 grams, more preferably at least 15 grams, most preferably at least 20 grams.
The term xe2x80x9c% elongationxe2x80x9d as used herein and in the appended claims is measured when a bioadhesive, closed-cell foam film, sustained release, delivery device of the present invention snaps as sufficient force is applied to exceed the elastic limit thereof.
The term xe2x80x9cmodulusxe2x80x9d as used herein and in the appended claims is a measurement of the stiffness of a bioadhesive, closed-cell foam film, sustained release, delivery device of the present invention.
The term xe2x80x9cmucosal tissuexe2x80x9d as used herein and in the appended claims means any moist mucosal surface of the subjects body as deemed appropriate for the systemic or local delivery of an active agent or combination of active agents including oral, nasal, vaginal, rectal and ocular tissues. The term xe2x80x9coral tissue(s)xe2x80x9d as used herein and in the appended claims includes lingual, sub-lingual, buccal, gingival and palatal surfaces; most preferably lingual, sub-lingual and buccal surfaces.
The term xe2x80x9cpermeation enhancerxe2x80x9d as used herein and in the appended claims means a natural or synthetic molecule which facilitates the absorption of a given active agent or combination of active agents through a mucosal tissue.
The term xe2x80x9crelease periodxe2x80x9d as used herein and in the appended claims means the period of time subsequent to administration of a bioadhesive, closed-cell foam film, sustained release, delivery devices of the present invention during which the delivery device releases an active agent or combination of active agents to a subject.
The term xe2x80x9csubjectxe2x80x9d as used herein and in the appended claims means an animal, preferably a mammal, most preferably a human.
The term xe2x80x9csustained releasexe2x80x9d as used herein and in the appended claims means the continual release of an active agent or combination of active agents over a period of time.
The term xe2x80x9ctensile strengthxe2x80x9d as used herein and in the appended claims is expressed in pounds per square inch (psi) and is the property of a bioadhesive, closed-cell foam film, sustained release, delivery device of the present invention that requires a load to cause load deformation failure of said film.
The term xe2x80x9cthicknessxe2x80x9d as used herein and in the appended claims by measurements in mil (a mil=one thousandth of an inch) is determined when a bioadhesive, closed-cell foam film, sustained release, delivery device of the present invention is placed between two microscopic slides.
The term xe2x80x9cwater contentxe2x80x9d as used herein and in the appended claims is the % residual water content per unit dose as measured to the Karl Fisher method and expressed as percent of the dry weight of a bioadhesive, closed-cell foam film, sustained release, delivery device of the present invention.
The term xe2x80x9czero order releasexe2x80x9d in relation to release kinetics as used herein and in the appended claims means that the rate of release of the active agent or active agents from a delivery device is a linear function with time.
In a preferred embodiment of the present invention, bioadhesive, closed-cell foam film, sustained release, delivery devices are provided which contain: (a) an active agent or combination of active agents, (b) a nonionic polymer or combination of nonionic polymers, (c) an anionic polymer or combination of anionic polymers, (d) a softening agent or combination of softening agents, (e) a swelling modifier or combination of swelling modifiers, (f) a chelating agent or combination of chelating agents, (g) a buffering agent or combination of buffering agents and (h) a foaming agent or combination of foaming agents. In a preferred aspect of this embodiment, the mass ratio of (i) the nonionic polymer or combination of nonionic polymers to (ii) the an anionic polymer or combination of anionic polymers in the delivery devices of the present invention preferably should be in the range of 1:6 to 6:1. In another preferred aspect of this embodiment, the mass ratio of (i) the swelling modifier or combination of swelling modifiers to (ii) the combination of the nonionic polymer or combination of nonionic polymers and the anionic polymer or combination of anionic polymers in the delivery devices of the present invention preferably should be in the range of 1:100 to 1:10. In yet another preferred aspect of this embodiment, the delivery devices of the present invention comprise multiple layers; most preferably, the delivery devices of the present invention preferably comprise a single layer. In still another preferred aspect of this embodiment, the delivery devices of the present invention preferably have a density of at least 0.2 grams/cm3; most preferably, the delivery devices of the present invention have a density in the range of 10 to 90% of the density of an identical non-foamed composition.
The bioadhesive, closed-cell foam film, sustained release, delivery devices of the present invention preferably contain 0.01 to 50 wt % of an active agent or combination of active agents.
The bioadhesive, closed-cell foam film, sustained release, delivery devices of the present invention preferably contain 10 to 60 wt % of a nonionic polymer or combination of nonionic polymers.
The bioadhesive, closed-cell foam film, sustained release, delivery devices of the present invention preferably contain 10 to 60 wt % of an anionic polymer or combination of anionic polymers.
The bioadhesive, closed-cell foam film, sustained release, delivery devices of the present invention preferably contain 5 to 40 wt % of a softening agent or combination of softening agents.
The bioadhesive, closed-cell foam film, sustained release, delivery devices of the present invention preferably contain 0.1 to 10 wt % of a swelling modifier or combination of swelling modifiers.
The bioadhesive, closed-cell foam film, sustained release, delivery devices of the present invention preferably contain 0.01 to 5 wt % of a chelating agent or combination of chelating agents.
The bioadhesive, closed-cell foam film, sustained release, delivery devices of the present invention preferably contain 0.1 to 10 wt % of a buffering agent or combination of buffering agents.
The bioadhesive, closed-cell foam film, sustained release, delivery devices of the present invention preferably contain 0.1 to 5 wt % of a foaming agent or combination of foaming agents.
The bioadhesive, closed-cell foam film, sustained release, delivery devices of the present invention may optionally contain additional ingredients, including: taste modifying agents, coloring agents, preservatives and permeation enhancers.
In another preferred embodiment of the present invention, bioadhesive, closed-cell foam film, sustained release, delivery devices are provided which contain: (a) 0.01 to 50 wt % of an active agent or combination of active agents, (b) 10 to 60 wt % of a nonionic polymer or combination of nonionic polymers, (c) 10 to 60 wt % of an anionic polymer or combination of anionic polymers, (d) 5 to 40 wt % of a softening agent or combination of softening agents, (e) 0.1 to 10 wt % of a swelling modifier or combination of swelling modifiers, (f) 0.01 to 5 wt % of a chelating agent or combination of chelating agents, (g) 0.1 to 10 wt % of a buffering agent or combination of buffering agents and (h) 0.1 to 5 wt % of a foaming agent or combination of foaming agents. In a preferred aspect of this embodiment, the mass ratio of (i) the nonionic polymer or combination of nonionic polymers to (ii) the anionic polymer or combination of anionic polymers in the delivery devices of the present invention preferably should be in the range of 1:6 to 6:1. In another preferred aspect of this embodiment, the mass ratio of (i) the swelling modifier or combination of swelling modifiers to (ii) the combination of the nonionic polymer or combination of nonionic polymers and the anionic polymer or combination of anionic polymers in the delivery devices of the present invention preferably should be in the range of 1:100 to 1:10. In yet another preferred aspect of this embodiment, the delivery devices of the present invention may comprise multiple layers. Most preferably, the delivery devices of the present invention comprise a single layer. In still yet another preferred aspect of this embodiment, the delivery devices of the present invention preferably have a density of at least 0.2 grams/cm3. Most preferably, the delivery devices of the present invention preferably have a density in the range of 10 to 90% of the density of an identical non-foamed composition.
In another embodiment of the present invention, a method for delivering an active agent or combination of active agents to a subject is provided, wherein a bioadhesive, closed cell foam film, sustained release, delivery device is administered to a mucosal tissue of the subject; wherein the delivery device contains: (a) 0.01 to 50 wt % of an active agent or combination of active agents, (b) 10 to 60 wt % of a nonionic polymer or combination of nonionic polymers, (c) 10 to 60 wt % of an anionic polymer or combination of anionic polymers, (d) 5 to 40 wt % of a softening agent or combination of softening agents, (e) 0.1 to 10 wt % of a swelling modifier or combination of swelling modifiers, (f) 0.01 to 5 wt % of a chelating agent or combination of chelating agents, (g) 0.1 to 10 wt % of a buffering agent or combination of buffering agents and (h) 0.1 to 5 wt % of a foaming agent or combination of foaming agents; and wherein the delivery device adheres to the mucosal tissue. In a preferred aspect of this embodiment, the mucosal tissue to which the delivery device is adhered is selected from the group including: oral, nasal, vaginal, rectal and ocular tissues; most preferably oral or vaginal tissues. In another preferred aspect of this embodiment, the delivery device provides a sustained, controlled release of an active agent or combination of active agents to the subject for a release period of at least 10 minutes, more preferably for a release period of 10 minutes to 168 hours, most preferably for a release period of at least 3 hours to a few days depending on the site of application. In another preferred aspect of this embodiment, the release kinetics of the active agent or combination of active agents from the delivery device should be near zero-order. In yet another preferred aspect of this embodiment, the delivery device completely dissolves or erodes from the mucosal tissue to which it is administered without leaving a residue. In still another preferred aspect of this embodiment, the delivery device releases the active agent or combination of active agents from all external surfaces of the delivery device.